Mantle cell lymphoma (MCL) is a mature B-cell Non-Hodgkin-Lymphoma that involves the lymphoid tissues, gastrointestinal tract, blood, and bone marrow. MCL is responsive to chemoimmunotherapy but most patients relapse within a few years. Thus MCL has a relatively short median overall survival of 5-7 years, which is amongst the shortest of all B-cell lymphomas. Bortezomib (Velcade) induces responses in 30-50% of patients with relapsed disease and is equally effective in patients sensitive or refractory to prior therapy. To investigate whether the addition of bortezomib to standard chemoimmunotherapy could improve the depth of response and extend the progression free survival we initiated a single center study combining bortezomib with the EPOCH-Rituximab regimen (trial registered as NCT00131976; lead investigator Wyndham Wilson, NCI). For the first cycle bortezomib was given as single agent on day 1, 4, 8, 11 followed by 6 cycles of combination therapy with bortezomib on day 1 and 4 of 21 day cycles. Of the first 38 patients, 63% achieved a complete response, 29% a PR and 3 (8%) did not respond. Responding patients are randomized to maintenance bortezomib for up to 18 months or observation. The trial is ongoing and we continue to collect samples for further analysis correlative studies focused on the effect of bortezomib single agent. We use gene expression profiling to systematically study the effect of proteasome inhibition on the tumor biology of MCL. We hypothesized that resistant tumors preferentially upregulate homeostatic responses to survive proteasome inhibition. Surprisingly, we found the opposite: sensitive tumors strongly upregulated anti-oxidant genes, and proteasome components, while resistant cells showed minimal gene expression changes in response to bortezomib. Furthermore, we found that increased expression of anti-oxidant genes in unstressed cells correlated with decreased sensitivity to proteasome inhibition. To further investigate the mechanisms of bortezomib resistance we generated an in vitro model of bortezomib-adapted MCL cell lines that were 40-80 fold less sensitive to bortezomib than the parental cells. These bortezomib resistant sublines showed increased proteasome activity, survived at lower proteasome capacity and showed characteristics of plasmacytic differentiation. Fresh tumor cells from MCL patients with poor clinical response to bortezomib also expressed plasmacytic features. Additional studies support the conclusion that plasmacytic differentiation in the absence of an increased secretory load can enable cells to withstand the stress of proteasome inhibition and thus identify possible targets to enhance the therapeutic efficacy of proteasome inhibitors. The efficacy of ibrutinib, a Brutons tyrosine kinase inhibitor, in mantle cell lymphoma (MCL) contradicts the notion that MCL is a malignancy of nave B-cells. However, the role of B-cell receptor (BCR) signaling in MCL remains ill-defined. To interrogate the signaling pathways in MCL in vivo, we profiled gene expression in tumor samples concomitantly isolated from blood and lymph nodes. Expression data identified upregulation of BCR and NF-B signaling proliferation in lymph node-resident MCL cells compared to circulating cells. Activation of relevant signaling molecules in the lymph node confirmed the gene expression data. A subset of leukemic samples had apparent cell-autonomous BCR activation, and carried mutations and/or polymorphism in genes encoding pathway-specific regulatory molecules that may confer ibrutinib resistance. We found direct in vivo evidence for activation of the BCR and canonical NF-B pathways in MCL that, in the absence of activating mutations, depends upon the lymph node microenvironment. These findings provide a mechanistic explanation for the surprising efficacy of ibrutinib in treating this type of lymphoma. Mutations and single nucleotide polymorphisms in components of the BCR and NF-B pathways are associated with cell-autonomous signaling and influence the sensitivity of MCL cells to BCR signaling inhibitors.